Related Experiment Video

Updated: Aug 17, 2026

Immunofluorescence Imaging of DNA Damage and Repair Foci in Human Colon Cancer Cells
05:18

Immunofluorescence Imaging of DNA Damage and Repair Foci in Human Colon Cancer Cells

Published on: June 9, 2020

DNA-dependent protein kinase is a molecular target for the development of noncytotoxic radiation-sensitizing drugs

Eric T Shinohara1, Ling Geng, Jiahui Tan

  • 1Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-5671, USA.

Cancer Research
|June 17, 2005
PubMed

Insights

DNA-dependent protein kinase (DNA-PK) inhibitors like IC87361 radiosensitize tumors by targeting DNA double-strand break repair. This radiosensitization effect was eliminated in DNA-PK-deficient mice, confirming DNA-PK as a key target for radiation-sensitizing drugs.

Area of Science:

  • Oncology
  • Radiation Biology
  • Molecular Biology

Background:

  • DNA-dependent protein kinase (DNA-PK) plays a crucial role in repairing DNA double-strand breaks, making it vital for cell survival after radiation exposure.
  • Severe combined immunodeficient (SCID) mice, defective in DNA-PK, exhibit increased sensitivity to ionizing radiation compared to wild-type mice.
  • Targeting DNA-PK is a potential strategy for enhancing the efficacy of radiation therapy.

Purpose of the Study:

  • To investigate the radiosensitizing effect of the specific DNA-PK inhibitor, IC87361, in the absence of functional DNA-PK.
  • To evaluate the impact of IC87361 on tumor microvasculature radiosensitization in both wild-type and SCID mice.
  • To assess the therapeutic potential of combining radiation with IC87361 in preclinical tumor models.

Main Methods:

  • In vitro studies using wild-type C57BL6 and SCID cells to assess radiosensitivity in the presence of IC87361.
  • In vivo tumor vascular window model to evaluate IC87361-induced radiosensitization of tumor microvasculature.
  • Implantation of LLC and B16F0 tumors into SCID and wild-type mice to measure tumor growth delay after radiation and/or IC87361 treatment.

Main Results:

  • IC87361 enhanced radiation sensitivity in wild-type cells but not in SCID cells, indicating a DNA-PK-dependent mechanism.
  • IC87361 induced radiosensitization of tumor microvasculature in wild-type mice, mimicking the radiosensitive phenotype observed in SCID mice.
  • Combined treatment with radiation and IC87361 significantly increased tumor growth delay in SCID mice compared to radiation alone, with no observed cytotoxicity or toxicity in normal tissues.

Conclusions:

  • The radiosensitizing effect of IC87361 is dependent on the presence of functional DNA-PK.
  • DNA-PK is a validated target for developing novel radiation-sensitizing drugs.
  • Combining DNA-PK inhibitors with radiation therapy holds promise for cancer treatment, offering enhanced efficacy with minimal side effects.

More Related Videos

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
Nucleotide Excision Repair01:38

Nucleotide Excision Repair

DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Nucleotide Excision Repair01:08

Nucleotide Excision Repair

Overview